Under this NIAAA Center grant The Scripps Research Institute Alcohol Research Center proposes to continue its long-term, cooperative interdisciplinary research program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI- ARC will consist of 9 components. The Administrative Core resource (supervising six supporting resource units) and 7 independent collaborating research components as well as a separate Pilot Project Component are designed to stimulate new research directions and recruit new investigators to ethanol research. The TSRI-ARC research program remains strongly interdisciplinary, employing molecular, cellular, and cellular system and behavioral research methods on experimental animal subjects and human subjects. Three major subthemes emerging from our past 19 years of work within this Center will be continued: 1) the molecular, cellular, system mechanisms of the acute reinforcing actions of ethanol (intoxication) and its potential molecular, neurophysiologic, neuroendocrine, and behavioral concomitants (including reinforcing and aversive effects of acute intoxication, (Drs. Sanna, Gruol, Siggins, Henriksen, Rivier, and Weiss), 2) the molecular, cellular and system changes underlying the adaptive responses to the brain systems involve in ethanol reinforcement during alcohol dependence following chronic exposure (Drs. Sanna, Gruol, Siggins, Henriksen, Rivier, and Weiss, 3) the molecular, cellular and neuropsychological basis for susceptibility to alcohol dependence and relapse in humans (Drs. Sanna, Gruol, Siggins, Henriksen, Rivier, Weiss, Ehlers and Polich). Progress during the previous funding period including new advances in animal model development have lead to a focusing of the new proposed work to understanding the neurobiology of ethanol dependence and relapse (subthemes 2 and 3). Individual research components range from studies of the effects of chronic ethanol on neuroadaptive mechanisms involving neuronal transduction mechanisms at the cellular, neuroendocrine and neurobehavioral levels to clinical studies of vulnerability to dependence. The TSRI-ARC also supports 11 RO1, R20, R29, and U10 grants of the TSRI- ARC PIs, and other major alcohol research groups at the UCSD VA Medical Center and San Diego State University through the collaboration, training and information exchange of the Administrative Core Support Units. Research funded within this Center provides the basic research knowledge required from development of better understanding of the basis for susceptibility to alcoholism important for new treatments and prevention.